The predominant outcome of cardiovascular disease (CVD) is myocardial infarction (MI), where cardiomyocytes are deprived of oxygen. To study inter-individual differences in cardiomyocytes’ response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We characterized gene expression levels, chromatin accessibility, and methylation profiles in these cardiomyocytes in four culturing conditions that correspond to normoxia (10% O2), hypoxia (1% O2) and short or long-term re-oxygenation (back to 10% O2). In our population sample, 2,113 genes change their expression following hypoxia and short- or long-term re-oxygenation. Using available genotypes from all individuals, we identified 1,573 genes with a cis eQTL in at least one of the four culturing conditions. Taking into account the incomplete power to identify eQTLs in any given condition, we also identified 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of dynamic eQTLs, which are detected only following hypoxia, have not been previously annotated as eQTLs even in much larger collections of heart tissues. We did not detect differences in DNA methylation, or chromatin accessibility as the cells transitioned between normoxia and hypoxia, but we observed a change in chromatin accessibility in 831 genomic regions upon re-oxygenation. Differentially accessible regions are enriched for features of active regulatory regions, SINE elements, and E2F4 transcription factor binding sites . Finally, we found that genes associated with dynamic eQTLs are also associated with complex traits and disease. Our data thus demonstrate how unique genetic effects on gene expression, which are likely relevant for disease, can be uncovered under conditions of stress.
Overall design
We collected DNA methylation data from iPSC-derived cardiomyocytes under normoxia, hypoxia and at two re-oxygenation timepoints in 13 human individuals. Three individuals were replicated three times.
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